Functional and molecular characteristics of patient-derived xenografts of colon cancer.

Introduction: Colorectal carcinoma (CRC) is the second leading cause of cancer-related deaths worldwide. Patient-derived xenografts (PDX) subcutaneously implanted in nude mice are highly suitable tools to aid in the development of novel anti-cancer therapeutics as their response is a good predictor of clinical outcome. In the present study, a panel of colon cancer PDXs (CXFs) was characterized for their molecular profile and sensitivity to standard of care (SoC) drugs. Material and Methods: CRC samples from patients undergoing surgery were implanted subcutaneously in nude mice and sequentially passaged. Tumor material was collected for molecular profiling, including mutational analysis by Sanger sequencing and Sequenom OncoCarta panels I, II, III. The efficacy of the SoC drugs 5-fluoruracil, oxaliplatin, irinotecan, bevacizumab and cetuximab was tested in vivo. All compounds were administered at clinically relevant dose levels and schedules. The tumor load was determined by caliper measurements twice a week. Anti-tumor activity was determined by comparing the relative tumor load of test groups vs. the vehicle-treated control group. Tumors were considered sensitive if the minimal test / control (T/C [%]) value recorded during an experiment was smaller than 30%. For cytotoxic SoC drugs, sensitivity of CXFs were also analyzed in an ex vivo tumor colony assay (TCA). Results: 73 CRC patient samples were implanted within the framework of this study. Up to now, 65 of them were established as CXF corresponding to a take rate of 89%. Mutational analysis was performed for 58 CXFs. Regarding the RAS/RAF pathway, mutations were found in K-RAS (26 out of 58 CXFs, 45%), NRAS (3%) and BRAF (7%). Mutations in the AKT/PI3K pathway were also found (PTEN, 9% and PIK3CA, 17%). In addition, one CXF had an IDH1 mutation (2%). For all SoC drugs both sensitive and resistant CXFs were identified and given CXFs differed in their sensitivities to different SoC drugs. In vivo sensitivity data will be correlated with molecular characteristics of the tested CXFs and with their sensitivities determined in the TCA. Conclusion and Outlook: Due to the high take rate, our CXF panel represents a large proportion of clinical variants of CRC. We will describe mutation profiles and sensitivity profiles to SoC drugs used for colon cancer. Correlation of sensitivity data and molecular data may reveal interesting correlations and identify biomarkers predictive of response to SoC drugs and experimental compounds. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C8. Citation Format: Jianing M. Guo, Kerstin Klingner, Rebekka Krumbach, Armin Maier, Silvia Naus, Vincent Vuaroqueaux, Evelyn Lamy, Heiner Fiebig, Julia B. Schueler. Functional and molecular characteristics of patient-derived xenografts of colon cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C8.